1. Field of the Invention
The present invention relates to a pharmaceutical composition containing one or more quinazoline derivatives as an active ingredient, which has antagonistic activity against serotonin 5-HT3A and is effective for the prevention and treatment of central nervous system (CNS) diseases, including emesis, nausea, alcoholism, drug abuse, depression, compulsive neurosis, anxiety, seizure, Alzheimer's disease, Parkinson's disease, Huntington's chorea, psychosis, schizophrenia, suicidal tendency, sleep disorder, appetite disorder and migraine.
2. Description of the Background
Serotonin is known to play an important role in psychiatric disorders (e.g., depression, aggression, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency), degenerative nerve disorders (e.g., Alzheimer's disease, Parkinson's disease, Huntington's chorea, anorexia, polyphagia, insomnia, alcoholism-related disorders, cerebral vascular accidents, migraine, and various other pathologic conditions [Meltzer, Neuropsychopharmacology, 21:106S-115S (1999); Barnes & Sharp. Neuropsychopharmacology, 38:1083-1152 (1999): Glennon, Neurosci. Biobehavioral Rev., 14:35(1990)]. Serotonin (5-hydroxytryptamine, or 5-HT) receptors are present in human and animals, and play an important role in physiological and behavioral functions. Until now, about 15 genetically different 5-HT receptor subtypes have been cloned. Each subtype exhibits unique distribution and shows various preference and relationships for different ligands.
A serotonin 5-HT3 receptor is a ligand-gated ionotropic receptor which allows the passage of cations [Maricq et al, Science, 1991, 254, 432-437]. The 5-HT3 receptor is mainly found in the human CNS [Morales, M et al, J. Neurosci., 2002, 22, 6732-6741]. The 5-HT3A receptor subtype was first cloned in 1991 by Maricq et al [Maricq et al, Science, 1991, 254, 432-437], and is found in the peripheral and limbic areas of the brain, including cortex, amygdala, hippocampus, and so forth [Tecott et al, Pro. Natl. Acad. Sci. U.S.A. 1993, 90, 1430-1434].
The 5-HT3 receptor exists either as 5-HT3A homomer or 5-HT3A and 5-HT3B heteromer. Both have the 5-HT3A subtype and it is known that their function is mostly provided by 5-HT3A. According to physiological studies on the 5-HT3A receptor, ondansetron, granisetron, tropisetron, and the like are effective and selective antagonists of the receptor [Gaster et al, Med. Res. Rev. 1997, 17, 163-214]. Clinical researches on these compounds show that they provide excellent effect for the treatment or amelioration of emesis, nausea, etc., during the cancer chemotherapy. Further, the 5-HT3A receptor is associated with alcoholism, drug abuse, depression, cognitive performance, psychological anxiety, pain, and the like [Silverston et al, Exp. Opi. Ther. Patents 1996, 6, 471-481].